Tricyclic compounds

ABSTRACT

The invention relates to novel cholecystokinin antagonists of the formula ##STR1## wherein R 1  is aryl which may have suitable substituent(s), X is --O-- or ##STR2## in which R 3  is hydrogen or lower alkyl, A is bond; or methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene, each of which may have lower alkyl group(s), and 
     R 2  is heterocyclic(C 3  -C 6 ) alkenoyl or heterocycliciccarbonyl, or a pharmaceutically acceptable salt thereof, useful as a cholecystokinin antagonist.

This is a division of application Ser. No. 07/612,955, filed on Nov. 15,1990, now U.S. Pat. No. 5,155,101 which is a division of Ser. No.07/396,124, filed on Aug. 21, 1989, now U.S. Pat. No. 4,981,847.

This invention relates to new tricyclic compounds and pharmaceuticallyacceptable salts thereof.

More particularly, it relates to new tricyclic compounds andpharmaceutically acceptable salts thereof which are cholecystokinin(CCK) antagonists and therefore useful as therapeutical and/orpreventive agents for emesis, pancreatitis, satiety and appetitecontrol, pain control, insulinoma, gastroparesis, carcinoma of pancreas,gallbladder disease (e.g. acute cholecystitis, calculus, etc.),disorders associated with intestinal smooth muscle hyperactivity (e.g.irritable bowel syndrome, sphincter spasm, etc.), hyperinsulinemia,dyspepsia, nausea, etc.

The tricyclic compounds of this invention can be represented by thefollowing formula (I): ##STR3## wherein

R¹ is aryl which may have suitable substituent(s),

X is --O-- or ##STR4## (in which R³ is hydrogen or lower alkyl),

A is a bond or lower alkylene which may have lower alkyl group(s), and

R² is hydrogen or an acyl group.

According to the present invention, the new tricyclic compounds (I) canbe prepared by the processes which are illustrated in the followingscheme. ##STR5## wherein

R¹, A and X are each as defined above,

R⁴ is lower alkyl,

R_(a) ² is an acyl group,

R_(b) ² is acyl having a nitro group,

R_(c) ² is acyl having an amino group,

R⁵ is hydrogen or hydroxy(lower)alkyl,

R⁶ is hydrogen or (C₁ -C₅)alkyl,

R⁷ is lower alkyl,

R⁸ is lower alkyl,

X is halogen,

R⁹ is aryl,

R¹⁰ is hydrogen or (C₁ -C₅)alkyl,

R¹¹ is hydroxy or lower alkyl,

R_(d) ² is acyl having a protected carboxy group,

R_(e) ² is acyl having a carboxy group,

R_(f) ² is acyl having a protected amino group,

R_(g) ² is acyl having an acylamino group.

The starting compound (II) is novel and can be prepared by the followingprocesses. ##STR6## wherein

R¹, R⁴, A and X are each as defined above,

Y¹ is halogen,

R¹² is lower alkyl, and

Y² is halogen.

The starting compound (VIII) or a salt thereof can be prepared by themethods disclosed in the Preparations 1 and 2 described later or similarmanners thereto.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salts and include a metal salt such as analkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt(e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate,formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acidsalt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), asalt with an amino acid (e.g arginine, aspartic acid, glutamic acid,etc.), and the like

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), unlessotherwise indicated.

The term "higher" is intended to mean 7 to 20 carbon atoms, unlessotherwise indicated.

Suitable "aryl" for R¹ may include phenyl, naphthyl and the like, andsaid aryl group may have one or more (preferably 1 to 3) suitablesubstituent(s) such as halogen, amino, lower alkoxy, mono(or di ortri)halo(lower)alkyl or the like.

Suitable "halogen" and "halogen moiety" in the term "mono(or di ortri)halo(lower)alkyl" may include chlorine, bromine, fluorine and iodine

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy,hexyloxy and the like.

Suitable "lower alkylene" may include straight one having 1 to 6 carbonatom(s), such as methylene, ethylene, trimethylene, tetramethylene,pentamethylene or hexamethylene, preferably one having 1 to 3 carbonatom(s), and said lower alkylene group may have one or more (preferably1 to 3) lower alkyl group(s).

Suitable "lower alkyl" and "lower alkyl moiety" in the term "mono(or dior tri)halo(lower)alkyl" may include straight or branched one having 1to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like,preferably one having 1 to 4 carbon atom(s)

Suitable "acyl" may include carbamoyl, aliphatic acyl group and acylgroup containing an aromatic ring, which is referred to as aromaticacyl, or heterocyclic ring, which is referred to as heterocyclic acyl

Suitable example of said acyl may be -illustrated as follows :

Carbamoyl;

Alliphatic acyl such as lower or higher alkanoyl (e.g. formyl, acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl heptanoyl, octanoyl, nonanoyl, decanoyl,undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl,hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl,etc.);

lower or higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);

lower or higher alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl,etc.);

lower or higher alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl,etc.); or the like;

Aromatic acyl such as aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.);ar(lower)alkanoyl [e.g. phenyl(lower)alkanoyl (e.g. phenylacetyl,phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl,phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g. naphthylacetyl,naphthylpropanoyl, naphthylbutanoyl, etc ), etc.];

ar(lower)alkenoyl [e.g. phenyl(lower)alkenoyl (e.g. phenylpropenoyl,phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhenxenoyl,etc.), naphthyl(lower)alkenoyl (e.g. naphthylpropenoyl,naphthylbutenoyl, naphthylpentenoyl, etc.), etc.];

ar(lower)alkoxycarbonyl [e.g. phenyl(lower)alkoxycarbonyl (e.g.benzyloxycarbonyl, etc.), etc.];

aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.);

aryloxy(lower)alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.);

arylcarbamoyl (e.g. phenylcarbamoyl, etc.);

arylthiocarbamoyl (e.g. phenylthiocarbamoyl, etc.);

arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.);

arenesulfonyl (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.); or thelike;

Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower)alkanoyl (e.g. thienylacetyl, thienylpropanoyl, thienylbutanoyl,thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl,tetrazolylacetyl, etc.); heterocyclic(lower)alkenoyl (e.g.heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl (e.g.thiazolylglyoxyloyl, thienylglyoxyloyl, etc.); or the like; in whichsuitable heterocyclic moiety in the terms "heterocycliccarbonyl","heterocyclic(lower)alkanoyl", heterocyclic(lower)alkenoyl and"heterocyclicglyoxyloyl" as mentioned above means, in more detail,saturated or unsaturated, monocyclic or polycyclic heterocyclic groupcontaining at least one hetero-atom such as an oxygen, sulfur, nitrogenatom and the like. And, especially preferable heterocyclic group may beheterocyclic group such as unsaturated 3 to 8-membered more preferably 5or 6-membered heteromonocyclic group containing 1 to 4-nitrogen atom(s),for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl andits N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3,-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl,2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s),for example pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;unsaturated condensed heterocyclic group containing 1 to 4 nitrogenatom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;unsaturated 3 to 8-membered (more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; saturated 3 to 8-membered (more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to8-membered (more preferably 5 or 6-membered) heteromonocyclic groupcontaining 1 to 2 sulfur atom(s), for example, thienyl,dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensedheterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogenatom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;unsaturated 3 to 8-membered (more preferably 5 to 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.; unsaturated 3 to 8-membered (more preferably 5 or6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2sulfur atom(s), for example, dihydrooxathiinyl", etc.; unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atom(s), forexample, benzothienyl, benzodithiinyl, etc.; unsaturated condensedheterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s),for example, benzoxathiinyl, etc. and the like. The acyl moiety asstated above may have one to ten, same or different, suitablesubstituent(s) such as halogen (e.g. fluorine, chlorine, bromine oriodine), hydroxy, nitro, lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.); amino,protected amino, heterocyclic(lower)alkylamino wherein heterocyclic andlower alkyl moieties can be referred to the ones as mentioned above,lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, t-butoxy,pentyloxy, hexyloxy, etc.), carboxy, protected carboxy,N,N-di(lower)alkylamino(lower)alkyl (e.g. N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N,N-dipropylaminomethyl, N,N-dimethylaminoethyl,N,N-diethylaminoethyl, . N,N-dipropylaminoethyl,N,N-dimethylaminopropyl, N,N-diethylaminopropyl,N,N-dipropylaminopropyl, N,N-dibutylaminomethyl,N,N-dipentylaminomethyl, N,N-dihexylaminomethyl, etc.),hydroxyimino(lower)alkyl (e.g. hydroxyiminomethyl, hydroxyiminoethyl,hydroxyiminopropyl, hydroxyiminobutyl, hydroxyiminopentyl,hydroxyiminohexyl, etc.), arylimino(lower)alkyl [e.g.phenylimino(lower)alkyl (e.g. phenyliminomethyl, phenyliminoethyl,phenyliminopropyl, phenyliminobutyl, phenyliminopentyl,phenyliminohexyl, etc.), etc.], acyl such as lower alkanoyl (e.g.formyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, etc.),hydroxy(lower)alkylheterocyclic(lower)alkyl wherein lower alkyl andheterocyclic moieties can be referred to the ones as mentioned above,mono(or di or tri)halo(lower)alkyl, arylamino(e.g. phenylamino, etc.),or the like. Suitable "protected amino" may include acylamino and thelike. Suitable "acyl moiety" in the term "acylamino" can be referred tothe ones as mentioned above.

Suitable "protected carboxy" may include esterified carboxy and thelike.

Suitable example of the ester moiety of an esterified carboxy may be theones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propylester, isopropyl ester, butyl ester, isobutyl ester, tertbutyl ester,pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which mayhave at least one suitable substituent(s), for example, loweralkanoyloxy(lower)-alkyl ester [e.g. acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or2)-acetoxyethyl ester, 1(or 2 or 3)-acetoxypropyl ester, 1(or 2 or 3 or4)-acetoxybutyl ester, 1(or 2)-propionyloxyethyl ester, 1(or 2 or3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or2)-isobutyryloxyethyl ester, 1(or 2)-pivaloyloxyethyl ester, 1(or2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester,2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1(or2)-pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower)alkylester (e.g. 2-mesylethyl ester, etc.), mono(or di ortri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy(lower)alkylester (e.g methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethylester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester,1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(lower)alkylester, or (5-lower alkyl 2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester(e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g ethynylester, propynyl ester, etc.); ar(lower)alkyl ester which may have atleast one suitable substituent(s) such as mono(or di ortri)-phenyl(lower)alkyl ester which may have at least one suitablesubstituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzylester, phenethyl ester, trityl ester, benzhydryl ester,bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which mayhave at least one suitable substituent(s) (e.g. phenyl ester,4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester,mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.Preferred embodiments of the object compound (I) are as follows.

R¹ which may have halogen,

X is --O-- or ##STR7## in which R³ is hydrogen or lower alkyl),

A is a bond or lower alkylene which may have lower alkyl,

R² is hydrogen;

ar(lower)alkenoyl which may have 1 to 3 substituent(s) selected from thegroup consisting of halogen, hydroxy, nitro, lower alkyl, lower alkoxy,amino, protected amino and heterocyclic(lower)alkylamino [morepreferably phenyl(lower)alkenoyl which may have one or twosubstituent(s) selected from the group consisting of halogen, hydroxy,nitro, lower alkyl, lower alkoxy, amino, acylamino andimidazolyl(lower)-alkylamino, most preferably phenyl(lower)alkenoylwhich may have one or two substituent(s) selected from the groupconsisting of halogen, hydroxy, nitro, lower alkyl, lower alkoxy, amino,lower alkanoylamino and imidazolyl(lower)alkylamino];

heterocyclic(lower)alkenoyl which may have carboxy or protected carboxy[more preferably indolyl(lower)-alkenoyl which may have carboxy orprotected carboxy; imidazolyl(lower)alkenoyl; orquinolyl(lower)alkenoyl, most preferably indolyl(lower)alkenoyl whichmay have carboxy or esterified carboxy; imidazolyl(lower)alkenoyl; orquinolyl(lower)alkenoyl];

heterocycliccarbonyl which may haveN,N-di(lower)alkylamino(lower)-alkyl, hydroxyimino(lower)alkyl,arylimino(lower)alkyl, acyl orhydroxy(lower)alkylheterocyclic(lower)-alkyl [more preferablyindolylcarbonyl which may have N,N-di(lower)alkylamino(lower)alkyl,hydroxyimino(lower)alkyl, phenylimino(lower)alkyl, lower alkanoyl orhydroxy(lower)alkylpiperazinyl(lower)alkyl; quinolylcarbonyl; orindolinylcarbonyl]; aroyl which may have 1 to 3 substituent(s) selectedfrom the group consisting of halogen, amino and mono(or di ortri)halo(lower)alkyl [more preferably benzoyl which may have one or twosubstituent(s) selected from the group consisting of halogen, amino andmono(or di or tri)halo(lower)alkyl];

arylcarbamoyl which may have halogen or lower alkoxy [more preferablyphenylcarbamoyl which may have halogen or lower alkoxy];

arylamino(lower)alkanoyl [more preferably phenylamino(lower)alkanoyl];or

ar(lower)alkanoyl which may have amino or protected amino [morepreferably phenyl(lower)alkanoyl which may have amino or acylamino, mostpreferably phenyl(lower)alkanoyl which may have amino, loweralkoxycarbonylamino or phenyl-thiocarbamoylamino],

The processes for preparing the object compound (I) of the presentinvention are explained in detail in the following.

Process 1

The compound (Ia) or a salt thereof can be prepared by reacting thecompound (II) or a salt thereof with the compound (III) or a saltthereof.

This reaction is usually carried out in a solvent such as alcohol (e.g.,methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, methylene chloride, ethylene chloride, chloroform,diethyl ether or any other solvent which does not adversely affect thereaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process 2

The compound (Ib) or a salt thereof can be prepared by subjecting thecompound (Ia) or its reactive derivative at the amino group or a saltthereof to acylation reaction.

Suitable acylating agent to be used in the present acylation reactionmay include the compound of the formula: ##STR8## or its reactivederivative or a salt thereof.

Suitable reactive derivative at the amino group of the compound (Ia) mayinclude Schiff's base type imino or its tautomeric enamine type isomerformed by the reaction of the compound (Ia) with a carbonyl compoundsuch as aldehyde, ketone or the like; a silyl derivative formed by thereaction of the compound (Ia) with a silyl compound such asN,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide or the like;a derivative formed by the reaction of the compound (Ia) with phosphorustrichloride or phosgene, and the like.

Suitable salts of the compound (Ia) and (XV) can be referred to the onesas exemplified for the compound (I).

Suitable reactive derivative of the compound (XV) may include an acidhalide, an acid anhydride, an activated amide, an activated ester,isocyanate, and the like. The suitable example may be an acid chloridean acid azide; a mixed acid anhydride with an acid such as substitutedphosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphorrc acid, halogenated phosphoricacid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfonic acid (e.g. methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g.benzoic acid, etc.); a symmetrical acid anhydride; an activated amidewith imidazole, 4-substituted imidazole, dimethylpyrazole, triazole ortetrazole; or an activated ester (e.g. cyanomethyl ester, methoxymethylester, dimethyliminomethyl [(CH₃)₂ N⁺ ═CH--] ester, vinyl ester,propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester,phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with aN-hydroxy compound (e.g. N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole,N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.);substituted or unsubstituted aryl isocyanate; substituted orunsubstituted aryl isothiocyanate; and the like. These reactivederivatives can optionally be selected from them according to the kindof the compound (XV) to be used.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvents which donot adversely influence the reaction These conventional solvents mayalso be used in a mixture with water.

When the compound (XV) is used in free acid form or its salt form in thereaction, the reaction is preferably carried out in the presence of aconventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiim:ide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride; oxalyl chloride;triphenylphosphine; 2-ethyl-7-hydroxybenzisoxasolium salt;2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, orthe like. The reaction temperature is not critical, and the reaction isusually carried out under cooling to heating.

Process 3

The compound (Ia) or a salt thereof can be prepared by subjecting thecompound (Ib) or a salt thereof to deacylation reaction. Suitable methodof this reaction may include conventional one such as hydrolysis,reduction and the like.

(i) For Hydrolysis

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], the hydroxide orcarbonate or bicarbonate thereof, trialkylamine [e.g trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid,etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. Theelimination using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.]or the like ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc ], methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical and thereaction is usually carried out under cooling to warming.

(ii) For Reduction

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound(e.g chromium chloride, chromium acetate, etc ) and an organic orinorganic acid (e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), palladium catalysts (e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium palladium onbarium sulfate, palladium on barium carbonate, etc.), nickel catalysts(e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobaltcatalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts(e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reducedcopper, Raney copper, Ullman copper, etc.) and the like. The reductionis usually carried out in a conventional solvent which does notadversely influence the reaction such as water, methanol, ethanol,propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are in liquid, they can also be used as a solvent.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

Process 4

The compound (Id) or a salt thereof can be prepared by subjecting thecompound (Ic) or a salt thereof to reduction reaction. This reductionreaction can be referred to that of the aforementioned Process 3.

Process 5

The compound (If) or a salt thereof can be prepared by reacting thecompound (Ie) or a salt thereof with the compound (IV) or a salt thereofand the compound (V).

The reaction is usually carried out in a conventional solvent such asalcohol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, aceticacid, or any other solvent which does not adversely influence thereaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Process 6

The compound (Ig) or a salt thereof can be prepared by reacting thecompound (Ie) or a salt thereof with the compound (VI).

The reaction is usually carried out in a conventional solvent such asalcohol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, or anyother solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process 7

The compound (Ii) or a salt thereof can be prepared by subjecting thecompound (Ih) or a salt thereof to hydrolysis reaction This hydrolysisreaction can be referred to that of the aforementioned Process 3.

Process 8

The compound (Ij) or a salt thereof can be prepared by reacting thecompound (Ii) or a salt thereof with the compound (VII) or a saltthereof

The reaction is usually carried out in a conventional solvent such asalcohol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, aceticacid or any other solvent which does not adversely influence thereaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

Process 9

The compound (Il) or a salt thereof can be prepared by subjecting thecompound (Ik) or a salt thereof to elimination reaction of the carboxyprotective group. This reaction can be carried out in a similar mannerto that of aforementioned Process 3.

Process 10

The compound (Id) or a salt thereof can be prepared by subjecting thecompound (Im) or a salt thereof to elimination reaction of the aminoprotective group. This reaction can be carried out in a similar mannerto that of aforementioned Process 3.

Process 11

The compound (In) or a salt thereof can be prepared by subjecting thecompound (Id) or a salt thereof to acylation reaction. This reaction canbe carried out in a similar manner to that of aforementioned Process 2.

The processes for preparing the starting compound (II) are explained inthe following.

Process A--1

The compound (X) or a salt thereof can be prepared by reacting acompound (VIII) or a salt thereof with a compound (IX) or a salt thereof

This reaction can be carried out in accordance with the method disclosedin the Preparation 3 described later or a similar manner thereto.

Process A--2

The compound (XII) or a salt thereof can be prepared by reacting acompound (X) or a salt thereof with a compound (XI).

This reaction can be carried out in the presence or absence of aconventional solvent.

The reaction temperature is not critical and the reaction is usuallycarried out at ambient temperature, under warming or under heating.

Process A--3

The compound (XIII) or a salt thereof can be prepared by subjecting acompound (XII) or a salt thereof to hydrolysis.

The hydrolysis can be carried out in the presence of a base, andsuitable base may be the inorganic base such as alkali metal hydroxide(e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metalhydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkalimetal carbonate (e.g sodium carbonate, potassium carbonate, etc.),alkaline earth metal carbonate (e.g. magnesium carbonate, calciumcarbonate, etc.) or the like.

This reaction is usually carried out in a solvent such as water, alcohol(e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide,tetrahydrofuran, diethyl ether or any other solvent which does notadversely affect the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming

Process A--4

The compound (II) or a salt thereof can be prepared by reacting acompound (XIII) or a salt thereof with a compound (XIV).

This reaction is usually carried out in the presence of a base such astri(lower)alkylamine (e.g., trimethylamine, triethylamine,diisopropylethylamine, etc.), di(lower)alkylaniline (e.g.,dimethylaniline, etc.) or the like.

This reaction is usually carried out in a solvent such as benzene,N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylenechloride, chloroform, diethyl ether or any other solvent which does notadversely affect the reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

The object compound (I) and pharmaceutically acceptable salts thereofare CCK antagonists and therefore useful as therapeutical agents foremesis, pancreatitis, etc. Further, it is expected that the objectcompound (I) and pharmaceutically acceptable salts thereof have gastrinantagonism and are useful as therapeutical and/or preventive agents forulcers, excess gastric secretion, zollinger-Ellison Syndrome, etc. Inorder to show the utility of the object compound (I), somepharmacological activities of the representative compound thereof areshown in the following. [I] TEST COMPOUND

(1)(3RS)-1-(2-Fluorophenyl)-3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(hereinafter referred to as test compound A)

(2)(3S)-1-(2-Fluorophenyl)-3,4,6,7,-tetrahydro-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,1-jk][1,4]

benzodiazepine (hereinafter referred to as test compound B)

[II] TEST (A) CCK Receptor Antagonism in Isolated Fundic Circular Musclefrom Guinea Pig Stomach Test Method

The strip of circular muscle suspended in 25 ml organ bath containingKrebs' bicarbonate solution (NaCl 118 mM, KCl 4.8 mM, KH₂ PO₄ 1.2 mM,CaCl₂ 5 mM, NaHCO₃ 25 mM, glucose 11 mM and bovine serum albumin 0.1%)maintained at 37° C. and gassed with 95% O₂ and 5% CO₂.

The strip was placed under an initial tension of 0.5 g and equilibratedfor 60 minutes during which the bath volume was replaced every 15minutes. Isometric contraction was measured using a force transducer.CCK-8 (3.2×10⁻⁷ M) was added to the bathing solution and the contractileforce was measured After washing out CCK-8, test compound A (1×10⁻⁶ M)was added 5 minutes later, CCK-8 was added and the contractile force wasmeasured CCK antagonism was calculated by comparing the contractileforce induced by CCK in the absence or presence of test compound A.

Test Result

Inhibition (%) : 90.4

(B) Inhibition of Binding of [¹²⁵ I] CCK-8 to Rat Pancreatic CCKReceptors by Test Compound B (CCK Antagonism)

IC₅₀ : 6.7×10⁻¹⁰ M .

(C) Inhibition of Binding of [¹²⁵ I] CCK-8 to Guinea Pig CerebralCortical CCK Receptors by Test Compound B (CCK Antagonism)

IC₅₀ : 3.1×10⁻⁸ M

(D) Inhibitory Effect of Test Compound B on Caerulein-inducedPancreatitis in Mice

ED₅₀ : 0.022 mg/kg

(E) Effect of Test Compound B Upon CCK-8-Induced Inhibition of GastricEmptying in Mice (CCK Antagonism)

ED₅₀ : 0.010 mg/kg

The object compound (I) or pharmaceutically acceptable salts thereof canusually be administered to mammals including human being in the form ofa conventional pharmaceutical composition such as capsule,micro-capsule, tablet, granule, powder, troche, syrup, aerosol,inhalation, solution, injection, suspension, emulsion, suppository orthe like

The pharmaceutical composition of this invention can contain variousorganic or inorganic carrier materials, which are conventionally usedfor pharmaceutical purpose, such as excipient (e.g. sucrose, starch,mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate,calcium carbonate, etc.), binding agent (cellulose, methyl cellulose,hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic,polyethyleneglycol, sucrose, starch, etc.), disintegrator (.e.g. starch,carboxymethyl cellulose, calcium salt of carboxymethyl cellulose,hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calciumphosphate, calcium citrate, etc.), lubricant (e.g. magnesium stearate,talc, sodium laurylsulfate, etc.), flavoring agent (e.g. citric acid,mentol, glycine, orange powders, etc.), preservative (e.g. sodiumbenzoate, sodium bisulfite, methylparaben, propylparaben, etc.),stabilizer (e.g. citric acid, sodium citrate, acetic acid, etc.),suspending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminumstearate, etc.), dispersing agent, aqueous diluting agent (e.g. water),base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum,etc.).

The effective ingredient may usually be administered with a unit dose of0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the above dosagemay be increased or decreased according to age, weight, conditions ofthe patient or the administering method.

The following preparations and examples are given only for the purposeof illustrating the present invention in more detail.

PREPARATION 1

(1) To a solution of boron trichloride (4.5 ml) in toluene (30 ml) wasadded a solution of 3,4-dihydro-2H-1,4-benzoxazine. (5.4 g),benzonitrile (5.05 g) and toluene (19 ml) over a period of 1 hour at0°-5° C., and aluminum chloride (5.85 g) was added thereto. The mixturewas heated under reflux for 16 hours. The reaction mixture was cooled to5° C., and water (7 ml) was added thereto. After the addition of 2Nhydrochloric acid, the mixture was heated under reflux for 2.5 hours andthen cooled to 10° C. The separated organic layer and the extract fromthe aqueous layer with ethyl acetate were combined and washed withaqueous sodium hydroxide and water. The organic layer was dried overmagnesium sulfate and evaporated. The residue was chromatographed onsilica gel with an eluent of a mixture of n-hexane and ethyl acetate(10:1) to give 5-benzoyl-3,4-dihydro-2H-1,4-benzoxazine (5.7 g).

IR (Nujol) 3300, 1615, 1595, 1570, 1500 cm⁻¹

NMR (CDCl₃, δ) : 3.50-3.75 (2H, m), 4.20-4.45 (2H, m), 6.30-7.85 (8H,m), 8.35 (1H, br s)

The following compounds were obtained according to a similar manner tothat of Preparation 1(1).

(2) 7-(2-Fluorobenzoyl)indoline

IR (Nujol) : 3370, 1615, 1605, 1575, 1565, 1495 cm⁻¹

NMR (CDCl₃, δ) : 3.15 (2H, tri, J=8 Hz), 3.87 (2H, tri, J=8 Hz),6.33-6.70 (1H, m), 7.0-7.73 (7H, m)

(3) (2RS)-7-(2-Fluorobenzoyl)-2-methylindoline

mp: 64°-66° C.

IR (Nujol): 3360, 1630, 1570, 1480, 1460, 1444, 1343, 1290, 1243, 1215,1017, 753 cm⁻¹

NMR (CDCl₃, δ) : 1.37 (3H, d, J=6.8 Hz), 2.68 (1H, dd, J=16 Hz, 7 Hz),3.31 (1H, dd, J=16 Hz, 9 Hz), 4.0-4.6 (1H, m), 6.3-7.7 (8H, m)

PREPARATION 2

(1) To a solution of 5-benzoyl-3,4-dihydro-2H-1,4-benzoxazine (5.74 g),pyridine (1.9 g) and methylene chloride (100 ml) was dropwise added asolution of bromoacetyl bromide (5.82 g) in methylene chloride (5 ml) atroom temperature. After the mixture was stirred for 1.0 hour at the sametemperature, water (100 ml) was added thereto under stirring. Theorganic layer was separated, washed with water, dried over magnesiumsulfate and evaporated. The residue was crystallized with a mixture ofdiisopropyl ether and ethyl acetate. The crystals were collected byfiltration to give4-bromoacetyl-5-benzoyl-3,4-dihydro-2H-1,4-benzoxazine (6.0 g).

IR (Nujol) : 1675, 1663, 1580 cm⁻¹

NMR (DMSO-d₆, δ) : 3.70-4.25 (2H, m), 4.10 (2H, s), 4.30-4.65 (2H, m),6.85-7.90 (8H, m)

The following compounds were obtained according to a similar manner tothat of Preparation 2(1).

(2) 1-Bromoacetyl-7-(2-fluorobenzoyl)indoline

IR (Nujol) : 1660, 1655, 1602, 1582 cm⁻¹

NMR (CDCl₃, δ) : 3.20 (2H, tri, J=8 Hz), 3.75 (2H, s), 4.20 (2H, tri,J=8 Hz), 6.90-7.95 (7H, m)

(3) (2RS)-1-Bromoacetyl-7-(2-fluorobenzoyl)-2-methylindoline

mp : 110°-112° C.

IR (Nujol) : 1667, 1639, 1445, 1391, 1275, 1223, 985, 750 cm⁻¹

NMR (CDCl₃, δ) : 1.38 (3H, d, J=6.8 Hz), 2.69 (1H, d, J=16 Hz), 3.53(1H, dd, J=16 Hz, 8 Hz), 3.71 (2H, s), 4.67 (1H, broad quintet, J=7 Hz),6.9-8.0 (7H, m)

PREPARATION 3 ##STR9##

To a solution of sodium hydroxide (4.5 g), water (45 ml), hydroxyaminehydrochloride (8.95 g) and ethanol (45 ml) was added a mixture of1-bromoacetyl-7-benzoylindoline (8.6 g) and ethanol (30 ml) over aperiod of 15 minutes at 50°-55° C. The mixture was stirred for 1.0 hourat the same temperature. Then, conc. hydrochloric acid (6 ml) was addedto the reaction mixture. After stirring for 1.0 hour, the mixture wascooled in an ice-bath. The precipitates were collected by filtration,washed with ethanol and air-dried to give3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine2-oxide (5.25 g).

mp : 245°-250° C. (dec.)

IR (Nujol) 1663, 1590, 1515 cm⁻¹

NMR (DMSO-d₆, δ) : 3.16 (2H, tri, J=8 Hz), 4.18 (2H, tri, J=8 Hz), 4.63(2H, s), 6.60-7.42 (8H, m)

MASS: m/e =278 (M⁺)

The following compounds were obtained according to a similar manner tothat of Preparation 3(1). ##STR10##

2,3,5,6-Tetrahydro-5oxo-8-phenyl-1,4-oxazino-[2,3,4-jk][1,4]benzodiazepine 7-oxide

mp: 145°-150° C. (dec.)

IR (Nujol) : 1665, 1580, 1530 cm⁻¹

NMR (DMSO-d₆, δ) : 2.90-3.50 (1H, m), 4.0-5.15 (5H, m), 6.45-7.75 (8H,m)

MASS : m/e=294 (M⁺) ##STR11##

1-(2-Fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo-[3,2,1-jk][1,4]benzodiazepine2-oxide

IR (Nujol) : 1675, 1665, 1608, 1585, 1570, 1512, 1488 cm⁻¹

MASS : m/e =296 (M⁺) ##STR12##

(6RS)-1-(2-Fluorophenyl)-3,4,6,7-tetrahydro-6-methyl-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine2-oxide

mp : 184°-186° C. (dec.)

IR (Nujol) : 1670, 1608, 1448, 1370, 1282, 1260, 1220, 1178, 1040, 760cm⁻¹

NMR (CDCl₃, δ) : 1.40 (3H, d, J=6.4 Hz), 2.76 (1H, d, J=16 Hz), 3.58(1H, dd, J=16, 7.8 Hz), 4.6-5.4 (3H, m /4.79, ABq, 2H), 6.8-7.6 (7H, m)

PREPARATION 4

(1) A mixture of3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo-[3,2,1-jk][1,4]benzodiazepine2-oxide (5.96 g) and anhydride (42 ml) was stirred for 6.0 hours at roomtemperature. Then to the cooled reaction mixture was added diisopropylether (120 ml). The precipitates were collected by filtration, washedwith diisopropyl ether and air-dried to give(3RS)-3-acetoxy-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(6.24 g).

mp : 191°-193° C.

IR (Nujol) : 1735, 1700, 1610, 1570 cm⁻¹

NMR (DMSO-d₆, δ) : 2.22 (3H, s), 3.0-3.40 (2H, m), 5.70 (1H, s),3.70-4.10 (1H, m), 6.90-7.70 (8H, m), 4.20-4.60 (1H, m)

MASS : m/e=320 (M⁺)

The following compounds were obtained according to a similar manner tothat of Preparation 4(1).

(2)(6RS)-6-Acetoxy-2,3,5,6-tetrahydro-5-oxo-8-phenyl-1,4-oxazino[2,3,4-jk][1,4]benzodiazepine

IR (Nujol) 1727, 1680, 1603, 1580, 1565 cm⁻¹

NMR (DMSO-d₆, δ) : 2.25 (3H, s), 3.10-3.50 (1H, m), 3.90-4.90 (3H, m),6.03 (1H, s), 6.80-7.75 (8H, m)

(3)(3RS)-3-Acetoxy-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 1746, 1690, 1600, 1581 cm⁻¹

NMR (DMSO-d₆, δ) : 2.20 (3H, s), 2.90-3.60 (2H, m), 3.73-4.20 (1H, m),4.25-4.65 (1H, m), 5.80 (1H, s), 6.90-7.75 (7H, m)

PREPARATION 5

A solution of(6RS)-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-6-methyl-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepine2-oxide (14.26 g) in acetic anhydride (100 ml) was heated at 80° C.under stirring for 45 minutes. The reaction mixture was cooled, and theresultant precipitate was collected by filtration and washed withdiisopropyl ether to give a mixture (10 80g) of(3RS,6RS)-3-acetoxy-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-6-methyl-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepineand(3RS,6SR)-3-acetoxy-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-6-methyl-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepineas light yellow crystal.

mp : 214°-216° C.

IR (Nujol) : 1738, 1685, 1609, 1450, 1370, 1235, 1108, 1080, 793, 752cm⁻¹

NMR (CDCl₃, δ) : 1.28 (3H, d, J=6 Hz), 2.32 (3H, s), 2.69 (1H, d, J=16.5Hz), 3.50 (1H, dd, J=16.5 Hz, 9 Hz), 4.99 (1H, broad quintet, J=7.5 Hz),5.90 (1H, s), 7.0-7.8 (7H, m)

PREPARATION 6

(1) To a mixture of(3RS)-3-acetoxy-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(3.95 g) and ethanol (123 ml)-was added 1N aqueous sodium hydroxide(12.3 ml) at room temperature After stirring for 15 minutes, water (100ml) was added to the reaction mixture, and the mixture was adjusted topH 4.0 with 6N hydrochloric acid. The ethanol was evaporated, and theresultant precipitates were collected by filtration and dried overphosphorus pentoxide to give(3RS)-3,4,6,7-tetrahydro-3-hydroxy-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(3.36 g).

IR (Nujol) : 3160, 1690, 1600, 1580, 1563 cm⁻¹

NMR (DMSO-d₆, δ) : 3.0-3.50 (2H, m), 3.60-4.10 (1H, m), 4.20-4.60 (1H,m), 4.70 (1H, d, J=8 Hz), 6.26 (1H, d, J=8 Hz), 6.95-7.60 (8H, m)

The following compounds were obtained according to a similar manner tothat of Preparation 6(1).

(2)(6RS)-2,3,5,6-Tetrahydro-6-hydroxy-5-oxo-8-phenyl-1,4-oxazino[2,3,4-jk][1,4]benzodiazepine

mp : 205°-210° C. (dec.)

IR (Nujol) 1680, 1600, 1580, 1565 cm⁻¹

NMR (DMSO-d₆, δ) : 2.90-3.50 (1H, m), 4.0-5.0 (3H, m), 5.0 (1H, d, J=9Hz), 6 40 (1H, d, J=9 Hz), 6.75-7.70 (8H, m)

MASS : m/e=294 (M⁺)

(3) (3RS)-1-(2-Fluorophenyl)3,4,6,7-tetrahydro-3-hydroxy-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3425, 1665, 1609, 1595, 1582 cm⁻¹

NMR (DMSO-d₆, δ) : 3.03-3.50 (2H, m), 3.60-4.25 (1H, m), 4.25-4.70 (1H,m), 4.78 (1H, d, J=8 Hz), 6.40 (1H, d, J=8 Hz), 7.0-7.90 (7H, m)

(4) Mixture of(3RS,6RS)-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-3-hydroxy-6-methyl-4-oxopyrrolo[3,2,1-jk]-[1,4]benzodiazepineand(3RS,6SR)-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-3-hydroxy-6-methyl-4-oxopyrrolot][3,2,1-jk][1,4]benzodiazepine

mp : 186°-187° C.

IR (Nujol) 3400, 1660, 1610, 1450, 1385, 1345, 1296, 1250, 1142, 762,750 cm⁻¹

NMR (CDCl₃, δ) : 1.31 (3H, d, J=6 Hz), 2.72 (1H, d, J=16.5 Hz), 3.51(1H, dd, J=16.5 Hz, 9 Hz), 4.7-5.2 (3H, m,/4.85, s), 6.8-7.7 (7H, m)

EXAMPLE 1

(1) To a solution of(3RS)-3,4,6,7-tetrahydro-3-hydroxy-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(1.4 g) in tetrahydrofuran (40 ml) were added diisopropylethylamine(0.97 g) and mesyl chloride (0.86 g) at 5° C. Then, after the mixturewas stirred for 2.0 hours at room temperature, 9N ammonia in methanol(30 ml) was added to the cooled reaction mixture. The reaction mixturewas stirred for 1.5 hours at room temperature. After solvent wasevaporated, the residue was mixed with a mixture of water and ethylacetate under stirring. Then, the separated organic layer was dried overmagnesium sulfate and evaporated. The residue was chromatographed onsilica gel with an eluent of a mixture of chloroform and methanol (15:1)to give(3RS)-3-amino-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]-benzodiazepine(460 mg)

NMR (CDCl₃, δ) : 2.40 (2H, br s), 2.90-3.60 (2H, m), 3.73-4.15 (1H, m),4.35 (1H, s), 4.50-4.85 (1H, m), 6.93-7.65 (8H, m)

The following compounds were obtained according to a similar manner tothat of Example 1(1).

(2)(6RS)-6-Amino-2,3,5,6-tetrahydro-5-oxo-8-phenyl-1,4-oxazino[2,3,4-jk][1,4]benzodiazepine

NMR (CDCl₃, δ) : 2.85-3.50 (1H, m), 3.90-5.20 (6H, m), 6.80-8.0 (8H, m)

(3)(3RS)-3-Amino-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

NMR (CDCl₃, δ) : 2.63 (2H, br s), 3.03-3.50 (2H, m), 3.63-4.35 (1H, m),4.35-4.95 (1H, m), 4.45 (1H, s), 6.85-7.80 (7H, m)

(4) Mixture of(3RS,6RS)-3-amino-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-6-methyl-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepineand(3RS,6SR)-3-amino-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-6-methyl-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Neat) : 3350, 1688, 1610, 1445, 1220, 1042, 750 cm⁻¹

NMR (CDCl₃, δ) : 1.27 & 1.73 (total 3H, each d, J=6 Hz), 2.59 (2H, s),2.5-3.6 (2H, m), 4.30 & 4.47 (total 1H, each s), 4.5-5.2 (1H, m),6.8-7.7 (7H, m)

EXAMPLE 2 ##STR13##

A mixture of(3RS)-3-amino-3,4,6,7-tetrahydro-4-enylpyrrolo[3,2,1-jk][1,4]benzodiazepine(430 mg), indole-2-carboxylic acid (250 mg), 1-hydroxybenzotriazole (210mg) and N,N-dimethylformamide (5 ml) was stirred at 5° C., andN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (298 mg)and triethylamine (160 mg) were added thereto The mixture was stirredfor 1.0 hour at room temperature. Then, the reaction mixture was pouredinto a mixture of ethyl acetate and water. The organic layer wasseparated, washed with water, dried over magnesium sulfate andevaporated. The residue was chromatographed on silica gel with an eluentof a mixture of chloroform and ethyl acetate (10 1) to give(3RS)-3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(0.405 g).

mp : 180°-185° C. (dec.)

NMR (CDCl₃, δ) : 2.90-3.50 (2H, m), 3.75-4.20 (1H, m), 4.50-4.85 (1H,m), 5.65 (1H, d, J=8 Hz), 6.90-7 70 (13H, m), 8.03 (1H, d, J=8 Hz), 9.85(1H, br s)

MASS : m/e=420 (M⁺)

The following compounds were obtained according to a similar manner tothat of Example 2(1). ##STR14##

(6RS)-2,3,5,6-Tetrahydro-6-(2-indolylcarbonylamino)-5-oxo-8-phenyl-1,4-oxazino[2,3,4-jk][1,4]benzodiazepine

mp : 180°-185° C. (dec.)

NMR (DMS-d₆, δ): 3.10-3.50 (1H, m), 4.0-4.90 (3H, m), 5.76 (1H, d,J=8Hz), 6.80-7.75 (13H, m), 9.45 (1H, d, J=8Hz)

MASS : m/e=436 (M⁺) ##STR15##

(3RS)-1-Fluorophenyl)-3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 280°-285° C. (dec.)

IR (Nujol) : 3390, 3250, 1678, 1640, 1610, 1600, 1580, 1531, 1500, 1482cm⁻¹

NMR (DMSO-d₆, δ): 3.10-3.65 (2H, m), 3.70-4.20 (1H, m), 4.30-4.70 (1H,m), 5.57 (1H, d, J=8Hz), 6.90-7.75 (12H, m), 9.53 (1H, d, J=8Hz)

MASS m/e=438 (M⁺)

(4) Mixture of(3RS,6RS)-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-6methyl-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine and(3RS,6SR)-1-(2-fluorophenyl)-3,4-6,7-tetrahydro-3-(2-indolylcarbonyl-amino)-6-methyl-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : >250° C.

IR (Nujol) : 3400, 3270, 1675, 1638, 1610, 1532, 1450, 1373, 1340, 1225,1118, 770, 755, 738 cm⁻¹

NMR (DMSO-d₆, δ): 1.11 & 1.54 (total 3H, each d, J=6Hz), 2.5-3.8 (2H,m), 4.5-5.1 (1H, m), 5.43 & 5.47 (total 1H, each d, J=8Hz), 6.9-7.7 (7H,m), 9.43 (1H, d, J=8Hz), 11.6 (1H, br s)

MASS : m/e=452(M⁺)

Preparation 7

The following compound was obtained according to a similar manner tothat of Preparation 1(1).

8-(2-Fluorobenzoyl)-1,2,3,4-tetrahydroquinoline

IR (Nujol): 3300, 3060, 1615, 1609, 1580, 1510, 1490 cm⁻¹

NMR (CDCl₃, δ): 1.70-2.10 (2H, m), 2.65-2.95 (2H, m), 3.35-3.65 (2H, m),6.20-6.48 (1H, m), 6.95-7.75 (6H, m), 9.05 (1H, br s)

Preparation 8

The following compound was obtained according to a similar manner tothat of Preparation 2(1).

1-Bromoacetyl-8-(2-fluorobenzoyl)-1,2,3,4-tetrahydroquinoline

NMR (CDCl₃, δ): 1.45-4.45 (8H, m), 6.90-7.95 (7H, m)

Preparation 9

The following compound was obtained according to a similar manner tothat of Preparation 3(1). ##STR16##1-(2-Fluorophenyl)-3,4,7,8-tetrahydro-4-oxo-6H-pyrido[3,2,1-jk][1,4]benzodiazepine2-oxide

NMR (DMSO-d₆, δ): 1.65-2.35 (2H, m), 2.70-3.50 (3H, m), 4.25-4.80 (1H,m), 4.48, 4.88 (2H, ABq, J=12Hz), 6.75-7.70 (7H, m)

Preparation 10

The following compound was obtained according to a similar manner tothat of Preparation 4(1).

(3RS)-3-Acetoxy-1-(2-fluorophenyl)-3,4,7,8-tetrahydro-4-oxo-6H-pyrido[3,2,1-jk][1,4]benzodiazepine

NMR (DMSO-d₆, δ): 1.65-2.40 (2H, m), 2.23 (3H, s), 2.75-3.85 (3H, m),4.15-4.70 (1H, m), 5.80 (1H, s), 6.95-7.85 (7H, m)

Preparation 11

The following compound was obtained according to a similar manner tothat of Preparation 6(1).

(3RS)-1-(2-Fluorophenyl)-3,4,7,8-tetrahydro-3-hydroxy-4-oxo-6H-pyrido[3,2,1-jk][1,4]benzodiazepine

NMR (DMSO-d₆, δ): 1.63-2.40 (2H, m), 2.75-3.50 (3H, m), 4.0-4.75 (1H,m), 4.83 (1H, d, J=9Hz), 6.35 (1H, d, J=9Hz), 6.90-7.90 (7H, m)

MASS: m/e=310 (M⁺)

EXAMPLE 3

The following compound was obtained according to a similar manner tothat of Example 1(1).

(3RS)-3-Amino-1-(2-Fluorophenyl)-3,4,7,8-tetrahydro-4-oxo-6H-pyrido[3,2,1-jk][1,4]benzodiazepine

NMR (CDCl₃, δ): 1.60-2 50 (2H, m), 2.6-3.55 (3H, m), 3.08 (2H, s),4.25-4.85 (1H, m), 4.55 (1H, s), 6.80-7.85 (7H, m)

EXAMPLE 4

(1) To a solution of(3RS)-3-amino-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(28.54 g) in N,N-dimethylformamide (285 ml) were addedN-tert-butoxycarbonyl-L-phen-vlalanine (27.33 g), 1-hydroxybenzotriazole(13.92 g) and N,N'-dicyclohexylcarbodiimide (21.25 g) under stirring atambient temperature. The mixture was stirred for two hours under thesame conditions and the resultant precipitates were filtered off. Thefiltrate and the washings (ethyl acetate) were combined and poured intoa mixture of ethyl acetate (500 ml) and water (500 ml) under stirring.The separated organic layer was washed with water, aqueous sodiumbicarbonate and water. After being dried over magnesium sulfate, theorganic solvent was removed under reduced pressure The residue waschromatographed on silica gel with an eluent of a mixture of chloroformand ethyl acetate (10:1) to give a mixture (48.82 g) of(3R)-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepineand(3S)-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepineas amorphous substance.

NMR (CDCl₃, δ): 1.41 and 1.43 (9H, each s), 2.9-3.5 (4H, m), 3.8-4.0(1H, m), 4.6-4.7 (2H, m), 5.0-5.1 (1H, broad s), 5.4 (1H, d, J=8Hz),7.0-7.8 (14H, m)

The following compound was obtained according to a similar manner tothat of Example 4(1).

(2) Mixture of(3R)-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepineand(3S)-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

NMR (CDCl₃, δ): 1.40 (9H, s), 2.93-5.20 (9H, m), 6.85-7.90 (13H, m)

EXAMPLE 5

Hydrogen chloride was bubbled into a solution of a mixture (48.50 g) of(3R)-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepineand(3S)-3-[((2S)-2-tert-butoxycarbonylamino-3-phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepinein ethyl acetate (1.0 l) under cooling in an ice-bath and stirring.After the mixture was saturated with hydrogen chloride, the resultantmixture was stirred at ambient temperature for one hour. Hydrogenchloride was removed by bubbling nitrogen. To the resultant mixture wasadded water and the mixture was stirred well. The aqueous layer wasseparated and the organic layer was washed with water. The separatedaqueous layer and washings were combined, neutralized with 20% aqueoussodium hydroxide and extracted with ethyl acetate twice. After theextracts were dried over magnesium sulfate, the solvent was evaporatedunder reduced pressure to give solid. The solid was collected byfiltration and washed with a small amount of ethyl acetate and ethylether in turn to give crude compound (13.42 g), which was recrystallizedfrom ethanol to afford(3R)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo-[3,2,1-jk][1,4]benzodiazepine(11.33 g) as light pink fine needles.

mp : 94°-95° C.

IR (Nujol) : 3350, 3150, 1672, 1644, 1597, 1550, 1445, 1372, 1237, 734,699 cm⁻¹

NMR (CDCl₃, δ): 1.62 (2H, broad s), 2.74 (1H, dd, J=14.0, 10.5Hz),3.1-3.5 (3H, m), 3.75 (1H, dd, J=3.5, 10.5Hz), 3.92 (1H, q, J=10.5Hz),4.66 (1H, t, J=10.5Hz), 5.45 (1H, d, J=8.4Hz), 7.06-7.6 (13H, m), 8.94(1H, d, J=8.4Hz)

Mass : m/e=424 (M⁺)

On the other hand, the filtrate was evaporated under reduced pressureAfter the residue was triturated with a small amount of ethyl acetate,the precipitate was collected by filtration. Recrystallization fromethanol (two times) gave(3S)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(9.70 g) as colorless needles.

mp : 203°-204° C.

IR (Nujol) : 3340, 3250, 1680 (sh), 1674, 1660, 1596, 1485, 1445, 1393,1328, 890, 756, 732, 702 cm⁻¹

NMR (CDCl₃, δ): 1.47 (2H, broad s), 2.85 (1H, dd, J=14.0, 10.5Hz),3.1-3.5 (3H, m), 3.75 (1H, dd, J=3.5, 10.5Hz), 3.97 (1H, q, J=10.5Hz),4.64 (1H, t, J=10.5Hz), 5.47 (1H, d, J=8.4Hz), 7.1-7.6 (13H, m), 8.95(1H, d, J=8.4Hz)

MASS : m/e=424 (M⁺)

EXAMPLE 6

The following compounds were obtained according to a similar manner tothat of Example 5.

(3R)-3-[((2S)-2-Amino-3-phenylpropanoyl)amino]-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1jk][1,4]benzodiazepine

NMR (CDCl₃, δ): 1.63 (2H, s), 2.60-4.90 (8H, m), 5.48 (1H, d, J=8Hz),6.80-7.85 (12H, m), 9.0 (1H, d, J=8Hz)

(3S)-3-[((2S)-2-Amino-3-phenylpropanoyl]amino]-1(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

NMR (CDCl₃, δ): 1.65 (2H, s), 2.60-4.90 (8H, m), 5.50 (1H, d, J=8Hz),6.80-7.90 (12H, m), 8.95 (1H, d, J=8Hz)

EXAMPLE 7

To a solution of(3S)-3-[((2S)-2-amino-3-phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(2.91 g) in methylene chloride (60 ml) was added phenylisothiocyanate(1.08 g) and the mixture was heated to remove methylene chloride and theresultant residue was completely evaporated under reduced pressure. Theviscous residue was chromatographed on silica gel. The elution wascarried out with chloroform and a mixture of chloroform and methanol(50:1) to afford(3S)-3,4,6,7-tetrahydro-1-phenyl-3-[[(2S)-2-{N'-(phenyl)thioureido}-3-phenylpropanoyl]amino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(2.95 g) as an amorphous substance.

EXAMPLE 8

A solution of(3S)-3,4,6,7-tetrahydro-1-phenyl-3-[[(2S)-2-{N'-(phenyl)thioureido}-3-phenylpropanoyl]amino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(2.90 g) in trifluoroacetic acid (10 ml) was stirred for 0.5 hours at50° C. The reaction mixture was evaporated under reduced pressure todryness and the residue was chromatographed on silica gel with a mixtureof chloroform and methanol (15:1) as an eluent. The fractions containingthe desired product were combined and washed with diluted aqueous sodiumbicarbonate. The organic layer was separated, dried over magnesiumsulfate and evaporated to give(3S)-3-amino-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(0.97 g) as an amorphous substance.

NMR (CDCl₃, δ): 2.38 (2H, br s), 3.0-3.5 (2H, m), 3.8-4.15 (1H, m), 4.38(1H, s), 4.514 4.8 (1H, m), 6.95-7.65 (8H, m) [α]_(D) ²⁰ =-175.09°(c=0.518, CHCl₃)

EXAMPLE 9

(1) To a solution of(3R)-3-[((2S)-2-amino-3phenylpropanoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(1.99 g) in methylene chloride (30 ml) was added phenylisothiocyanate(0.76 g) and the mixture was heated to remove methylene chloride and theresultant residue was ccmpletely evaporated under reduced pressure. Theresidue was dissolved in trifluoroacetic acid (7 ml) and the mixture wasstirred at 50° C. for 25 minutes. Removal of trifluoroacetic acid gaveviscous oil, which was chromatographed on silica gel with a mixture ofchloroform and methanol (15:1) as an eluent. The fractions containingthe desired product were combined and washed with diluted aqueous sodiumbicarbonate. The organic layer was separated and dried over magnesiumsulfate. Removal of the solvent gave(3R)-3-amino-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(0.91 g) as an amorphous substance.

NMR (CDCl₃, δ): 2.40 (2H, br s), 3.0-3.5 (2H, m), 3.8-4.3 (1H, m), 4.40(1H, br s), 4.5-4.8 1H, m), 7.0-7.8 (8H, m)

[α]_(D) ²⁰ =146.44° (c=0.574, CHCl₃)

The following compounds were obtained according to a similar manner tothat of Example 9(1).

(2)(3S)-3-Amino-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

[α]_(D) ²⁵ =-73.4° (c=0.475, CHCl₃)

(3)(3R)-3-Amino-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

[α]_(D) ²⁵ =67° (c=0.432, CHCl₃)

EXAMPLE 10

(1) To a solution of 2-amino-4-chlorobenzoic acid (418.7 mg) andN-methylmorpholine (246.8 mg) in a mixture of methylene chloride andN,N-dimethylformamide (10:1, 35 ml) was dropwise added isobutylchloroformate (333.3 mg) under cooling at -10° C. in an ice-salt bathand stirring. The mixture was stirred at the same temperature for 15minutes and warmed to 0° C. To the resultant mixture was dropwise addeda solution of(3RS)-3-amino-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(554.7 mg) in a mixture of methylene chloride and N,N-dimethylformamide(10:1, 5 ml) under the same conditions. The mixture was stirred for onehour at the same temperature and 12 hours at ambient temperature.Methylene chloride was removed from the reaction mixture Ethyl acetateand an aqueous solution of sodium bicarbonate were added to the mixtureunder stirring. The separated organic layer was washed with water twiceand dried over magnesium sulfate. Removal of the solvent under reducedpressure afforded a brown oil (1.22 g), which was chromatographed onsilica gel with an eluent of chloroform. The fractions containing thedesired compound were combined and evaporated to give an amorphoussubstance, which was powdered by stirring in diisopropyl etherovernight. The white powder was collected by filtration and washed withdiisopropyl ether to give(3RS)-3-[(2-amino-4-chlorobenzoyl)amino]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(213.5 mg).

mp : 145°-148° C (dec.)

IR (Nujol) : 3410, 3320, 1685 (sh), 1675, 1640, 1610, 1505, 1447, 1373,1240, 1165, 918, 860, 832, 695 cm⁻¹

NMR (CDCl₃, δ): 3.0-3.4 (2H, m), 3.7-4.1 (1H, m), 4.4-4.8 (1H, m), 5.58(1H, d, J=8Hz), 5.68 (2H, br s), 6.6-7.6 (11H, m), 7.86 (1H, d, J=8Hz)

MASS : m/e=430 (M⁺)

The following compounds were obtained according to a ilar manner to thatof Example 10(1).

(2)(3RS)-3-[(2-Amino-4-chlorobenzoyl)amino]-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine.

mp : 200°-205° C.

IR (Nujol) : 3420, 3300, 1675, 1640, 1570, 1500, 1255, 915, 755 cm⁻¹

NMR (DMSO-d₆, δ) : 2.83-3.6 (2H, m), 3.6-4.7 (1H, m), 4.2-4.67 (1H, m),5.35 (1H, d, J=8Hz), 6.33-7.63 (11H, m), 7.72 (1H, d, J=9Hz), 6.22.(1H,d, J=8Hz)

MASS : m/e=447 (M⁺)

(3)(3RS)-3-((E)-Cinnamoylamino)-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepine

mp : 189°-190° C.

IR (Nujol) : 3290, 1675, 1650, 1620, 1530 cm⁻¹

NMR (CDCl₃, δ) : 3.0-3.6 (2H, m), 3.8-4.8 (1H, m), 5.55 (1H, d, J=8Hz),6.58 (1H, d, J=15Hz), 6.83-7.8 (15H, m)

MASS : m/e=425 (M⁺), 294 (M⁺ -131)

(4)(3RS)-1-(2-Fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-3-[(4-trifluoromethylbenzoyl)amino]pyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 199°-201° C.

IR (Nujol): 3300, 1670, 1640, 1530, 1325, 1150, 1120, 1065, 850 cm⁻¹

NMR (CDCl₃, δ) : 2.87-3.4 (2H, m), 3.8-4.23 (1H, m), 4.43-4.8 (1H, m),5.55 (1H, d, J=8Hz), 6.8-8.13 (12H, m)

MASS : m/e=467 (M⁺)

(5)(3RS)-3,4,6,7-Tetrahydro-1-phenyl-3-[(4-trifluoromethylbenzoyl)amino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 232°-235° C.

IR (Nujol) : 3350, 3230, 1690, 1660, 1545, 1320, 1240, 1170, 1125, 1060,860 cm⁻¹

NMR (CDCl₃, δ) : 3.07-3.49 (2H, m), 3.92-4.08 (1H, m), 4.62-4.74 (1H,m), 5.62 (1H, d, J=8Hz), 7.10-8.11 (13H, m)

MASS : m/e=449 (M⁺)

(6)(3RS)-3-((E)-Cinnamoylamino)-3,4,6,7-tetrahydro-1-phenyl-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 224°-226° C.

IR (Nujol) : 3300, 1680, 1655, 1625, 1510, 1210 cm⁻¹

NMR (CDCl₃, δ) : 2.77-3.5 (2H, m), 3.67-4.1 (1H, m), 4.4-4.77 (1H, m),5.48 (1H, d, J=8Hz), 6.43-7.77 (16H, m)

MASS : m/e=407 (M⁺)

EXAMPLE 11

(1) To a solution of(3RS)-3-amino-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(0.56 g) in dry tetrahydrofuran (8 ml) was added 4-chlorophenylisocyanate (0.31 g) under stirring at ambient temperature. To themixture was added an additional tetrahydrofuran (4 ml). The mixture wasstirred for 4 hours at ambient temperature. The white precipitates werecollected by filtration, washed with cold tetrahydrofuran and diethylether successively and dried to afford(3RS)-3-[N'-(4chlorophenyl)ureido]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(0.48 g) as a white powder.

mp : 263°-265° C. (dec.)

IR (Nujol) : 3350, 3250, 1680 (sh), 1672, 1645, 1600, 1547, 1487, 1444,1396, 1388, 1302, 1217, 1166, 825, 695 cm⁻¹

NMR (DMSO-d₆, δ) : 3.1-3.6 (2H, m), 3.7-4.3 (1H, m), 4.3-4.7 (1H, m),5.18 (1H, d, J=8Hz), 7.2-7.8 (13H, m), 9.27 (1H, broad s)

MASS : m/e=430 (M⁺)

The following compounds were obtained according to a similar manner tothat of Example 11(1).

(2)(3RS)-3-[N'-(4-Chlorophenyl)ureido]-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 262°-264° C. (dec.)

IR (Nujol) : 3250, 1675, 1640, 1600, 1545, 1490, 1300, 1215, 820, 750cm⁻¹

NMR (DMSO-d₆, δ) : 2.93-3.5 (2H, m), 3.67-4.1 (1H, m), 4.23-4.6 (1H, m),5.08 (1H, d, J=8Hz), 6.9-7.67 (12H, m), 9.1 (1H, br s)

(3)(3RS)-3-[N'-(2-Chlorophenyl)ureido]-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 258°-260° C. (dec.)

IR (Nujol) : 3250, 1680, 1640, 1580, 1550 cm⁻¹

NMR (DMSO-d₆, δ) : 2.87-3.5 (2H, m), 3.7-4.1 (1H, m), 4.2-4.63 (1H, m),5.13 (1H, d, J=8Hz), 6.8-7.7 (11H, m), 8.07 (1H, d, J=8Hz), 8.43 (1H, d,J=9Hz), 8.63 (1H, br s)

(4)(3RS)-3-[N'-(2-Chlorophenyl)ureido]-1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 240°-241° C.

IR (Nujol) : 3270, 1670, 1640, 1590, 1535 cm⁻¹

NMR (DMSO-d₆, δ) : 3.0-3.5 (2H, m), 3.83-4.67 (1H, m), 5.17 (1H, d,J=8Hz), 6.9-7.63 (10H, m), 8.08 (1H, d, J=9Hz), 8.45 (1H, d, J=8Hz),8.63 (1H, s)

(5)(3RS)-1-(2-Fluorophenyl)-3,4,6,7-tetrahydro-3-[N'-(3-methoxyphenyl)ureido]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 242°-243° C.

IR (Nujol) : 3280, 1670, 1630, 1605, 1550, 1285, 1210, 1155 cm⁻¹

NMR (DMSO-d₆, δ) : 2.9-3.5 (2H, m), 3.67 (3H, s), 3.8-4.7 (2H, m), 5.13(1H, d, J=8Hz), 6.4-7.7 (12H, m), 9.0 (1H, br s)

MASS : m/e=444 (M⁺)

(6)(3RS)-3,4,6,7-Tetrahydro-3-[N'-(3-methoxyphenyl)ureido]-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 247°-248° C.

IR (Nujol) : 3260, 1670, 1640, 1555, 1515, 1220, 1150, 1040 cm⁻¹

NMR (DMSO-d₆, δ) : 2.7-3.3 (2H, m), 3.5 (3H, s), 3.6-3.9 (1H, m),4.1-4.5 (1H, m), 4.95 (1H, d, J=8Hz), 6.2-7.6 (13H, m), 8.85 (1H, br s)

MASS : m/e=426 (M⁺)

EXAMPLE 12

(1) To a solution of(3S)-3-amino-3,4,6,7-tetrahydro-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(0.97 g), indole-2-carboxylic acid (0.564 g), 1-hydroxybenzotriazole(472.5 mg) in N,N-dimethylformamide (10 ml) were addedN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (669.2 mg)and triethylamine (351.2 mg) under stirring at ambient temperature. Themixture was stirred for two hours under the same conditions. To thereaction mixture was added ethyl acetate. The mixture was washed withwater, an aqueous solution of sodium bicarbonate and water. The organiclayer was separated and dried over magnesium sulfate. Removal of thesolvent afforded an amorphous material (1.55 g), which waschromatographed on silica gel with a mixture of chloroform and ethylacetate (10:1) as an eluent to give an amorphous substance (1.39 g).This substance was triturated in diisopropyl ether and the resultantwhite powder was collected by filtration. The powder was stirred inwater for 2 days, collected again and dried under reduced pressure andheating to give (3S)-3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(optical purity : 98.4% e.e.) (1.12 g).

mp : 177°-180° C.

IR (Nujol) : 3230, 1675, 1638, 1600, 1530, 1445, 1372, 1300, 1235, 1110,745 cm⁻¹

NMR (CDCl₃, δ) : 3.0-3.5 (2H, m), 3.8-4.2 (1H, m), 4.5-4.85 (1H, m),5.68 (1H, d, J=7.5Hz), 7.0-7.8 (13H, m), 8.07 (1H, d, J=7.5Hz), 9.90(1H, br s)

MASS : m/e=420 (M⁺)

[α]_(D) ²⁰ =-63.8° (c=0.5 CHCl₃)

The following compounds were obtained according to a similar manner tothat of Example 12(1).

(2)(3R)-3,4,6,7-Tetrahydro-3-(2-indolylcarbonylamino)-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepine(optical purity : 97.74% e.e.)

mp : 171°-177° C. (dec.)

IR (Nujol) : 3230, 1674, 1638, 1600, 1530, 1445, 1370, 1300, 1236, 1112,745, 695 cm⁻¹

NMR (CDCl₃, δ) : 3.0-3.5 (2H, m), 3.8-4.16 (1H, m), 4.5-4.82 (1H, m),5.67 (1H, d, J=7.5Hz), 7.0-7.75 (13H, m), 8.08 (1H, d, J=7.5Hz), 9.95(1H, br s)

MASS : m/e=420 (M⁺)

[α]_(D) ²⁰ =64.88° (c=0.524, CHCl₃)

(3)(3S)-1-(2-Fluorophenyl)-3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,1-3k][1,4]benzodiazepine(optical purity : 97.8% e.e.)

mp : 270°-275° C.

NMR (DMSO-d₆, δ) : 3.0-3.65 (2H, m), 3.75-4.20 (1H, m), 4.30-4.70 (1H,m), 5.55 (1H, d, J=8Hz), 6.90-7.75 (12H, m), 9.53 (1H, d, J=8Hz), 11.65(1H, br s)

MASS : m/e=438 (M⁺)

[α]_(D) ²⁵ =19.8° (c=0.3, CHCl₃)

(4)(3R)-1-(2-Fluorophenyl)-3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(optical purity : 93.4% e.e.)

mp : 260°-265° C. (dec.)

NMR (DMSO-d₆, δ) : 3.0-3.65 (2H, m), 3.75-4.20 (1H, m), 4.30-4.70 (1H,m), 5.55 (1H, d, J=8Hz), 6.90-7.75 (12H, m), 9.53 (1H, d, J=8Hz), 11.63(1H, br s)

MASS : m/e=438 (M⁺)

[α]_(D) ²⁵ =-17.8° (c=0.3, CHCl₃)

EXAMPLE 13

The following compound was obtained according to a similar manner tothat of Example 2(1). ##STR17##

(3RS)-1-(2-Fluorophenyl)-3,4,7,8-tetrahydro-3-(2-indolylcarbonylamino)-4-oxo-6H-pyrido[3,2,1-jk][1,4]benzodiazepine

NMR (DMSO-d₆, δ) : 1.55-2.25 (2H, m), 2.75-3.30 (3H, m), 4.15-4.55 (1H,m), 5.53 (1H, d, J=8Hz), 6.85-7.70(12H, m), 9.40 (1H, d, J=8Hz)

MASS : m/e=452 (M⁺)

Preparation 12

A mixture of 7-cyanoindoline (4.32 g) and 50% aqueous sulfuric acid (40ml) was stirred at 110°-120° C. for 5.5 hours, cooled to 5° C. andadjusted to pH 7-8 with 24% aqueous sodium hydroxide. The mixture waswashed with ethyl acetate and the aqueous layer was adjusted to pH2.5-3.0 with 6N hydrochloric acid. The precipitates were collected byfiltration to give indoline-7-carboxylic acid (3.25 g).

IR (Nujol) : 3420, 2600, 1650, 1605, 1590 cm⁻¹

NMR (CDCl₃, δ) : 3.07 (2H, tri, J=18Hz), 3.74 (2H, tri J=18Hz),6.53-6.60 (1H, m), 7.17-7.25 (1H, m), 7.59-7.63(1H, m)

Preparation 13

A solution of methyl (E)-3-(2-aminophenyl)propenoate (531.6 mg) and4-formylimidazole (317.1 mg) in methanol (7.0 ml) was stirred at ambienttemperature for 18 hours. To the reaction mixture was added sodiumborohydride (56.5 mg) under stirring and cooling in an ice-bath. Afterthe mixture was stirred for 2 hours at ambient temperature, sodiumborohydride (56.5 mg) was added thereto. The mixture was stirred for 2hours at ambient temperature. To the reaction mixture was added aceticacid in order to decompose the excess sodium borohydride and themethanol was removed under reduced pressure. To the residue were addeddiluted hydrochloric acid and ethyl acetate under stirring. Theseparated aqueous layer was basified with aqueous sodium bicarbonate andextracted twice with ethyl acetate. The extract was washed with water,dried over magnesium sulfate and evaporated to give a residue, which wassubjected to column chromatography on silica gel with an eluent of amixture of chloroform and methanol (20:1) to afford pure methyl(E)-3-[2-(4-imidazolylmethylamino)phenyl] propenoate (0.7 g) as an oil.

NMR (CDCl₃, δ) : 3.75 (3H, s), 4.33 (2H, s), 4.51 (1H, broad), 6.31 (1H,d, J=15.7Hz), 6.68-7.58 (6H, m), 7.81 (1H, d, J=15.7Hz)

Preparation 14

To a solution of methyl(E)-3-[2-(4-imidazolylmethylamino)phenyl]propenoate (0.7 g) in methanol(7 ml) was added 1N sodium hydroxide aqueous solution (3 ml) and themixture was stirred for 20 hours. After removal of methanol from thereaction mixture, water was added to the residue. The mixture wasadjusted to pH 6 with acetic acid. The mixture was salted out andextracted with ethyl acetate 8 times. The extracts were combined anddried over magenessium sulfate. Removal of the solvent afforded anorange oil, which was dissolved in methanol (5 ml). To the solution wasadded an ethereal solution of hydrogen chloride. The resultantprecipitate was collected by filtration, washed with ether twice anddried to give (E)-3-[2-(4-imidazolylmethylamino)phenyl]propenoic aciddihydrochloride (0.29 g).

NMR (D₂ O, δ) : 4.65 (2H, S), 6.38 (1H, d, J=15.6Hz), 7.02-7.6.(5H, m),7.80 (1H, d, J=15.6Hz), 8.67 (1H, s)

EXAMPLE 14

The following compounds were obtained according to a similar manner tothat of Example 2(1).

(1) (3RS)-3,4,67-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-{2-(4-imidazolylmethylamino)phenyl}-propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepine

mp : 205°-210° C. (dec.)

IR (Nujol) : 3200, 2600, 1691, 1645, 1610, 1600, 1540, 1505 cm⁻¹

NMR (CDCl₃, δ) : 3.02-3.34 (2H, m), 3.85-4.01 (1H, m), 4.30 (2H, s),4.53-4.63 (2H, m), 5.54 (1H, d, J=7.4Hz), 6.49 (1H, d, J=15Hz),6.68-7.63 (14H, m), 7.76 (1H, d, J=7.4Hz), 7.78 (1H, d, J=15Hz)

(2)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-(7-indolinylcarbonylamino)-4-oxo-pyrrolo[3,2,1-jk]-[1,4]benzodiazepine

mp : 165°-170° C. (dec.)

IR (Nujol) : 3310, 1665, 1630, 1590, 1522 cm⁻¹

NMR (CDCl₃, δ) : 3.04 (2H, tri, J™8.4Hz), 3.14-3.20 (1H, m), 3.28-3.46(1H, m), 3.67 (2H, tri, J=8.4Hz), 3.96-4.12 (1H, m), 4.61-4.73 (1H, m),5.62 (1H, d, J=7.4Hz 6.29 (1H, bs), 6.58-6.66 (1H, m), 6.98-7.71 (9H,m), 7.92 (1H, d, J=7.4Hz)

MASS : m/e=440 (M⁺)

(3)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-(3-quinolylcarbonylamino)-4-oxo-pyrrolo[3,2,1-jk][1,4]benzodiazepinehydrochloride

mp : 198°-200° C.

IR (Nujol) : 3550-3100, 2700-2100, 1660, 1605, 1520 cm⁻¹

NMR (CDCl₃, δ) : 3.07-3.55 (2H, m), 3.95-4.2 (1H,m), 4.6-4.8 (1H, m),5.83 (1H, d, J=7.3Hz), 7.00-7.27 (4H, m), 7.51-7.69 (3H, m),7.85-7,92(1H, m), 8.04-8.11 (1H, m), 8.26 (1H, d, J=8Hz), 8.84 (1H, d,J=8.5Hz), 9.47 (1H, d, J=7Hz), 9.60 (1H, s), 9.79(1H, s)

(4)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(8-quinolyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepinehydrochloride

mp : 180°-185° C.

IR (Nujol) : 3280, 1668, 1647, 1623, 1540, 1450, 1372, 1212, 981, 767,748 cm⁻¹

NMR (DMSO-d₆, δ) : 3.11-3.49 (2H, m), 3.99 (1H, q, J=10.8Hz), 4.52 (1H,t, J=9.8Hz), 5.47 (1H, d, J=8.2Hz), 7.0-9.0 (15H m)

(5)(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(2-amino-4-chlorobenzoyl)amino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp : 217°-220° C.

IR (Nujol) : 3400, 3300, 1675, 1630, 1610 cm⁻¹

NMR (CDCl₃, δ) : 3.09-3.46 (2H, m), 3.97-4.12 (1H, m), 4.61-4.73 (1H,m), 5.58 (1H d, J=7.3Hz), 5.69 (2H, bs), 6.64-7 88 (1H m)

MASS : m/e=448 (M⁺)

[α]_(D) ²⁵ =60.59° (C=0.812, CHCl₃)

(6)(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-hydroxyphenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 178°-192° C. (dec.)

IR (Nujol) : 3400-3000, 1650, 1600 cm⁻¹

NMR (CDCl₃, δ) : 3.09-3.47 (2H, m), 3.97-4.12 (1H, m), 4.63-4.73 (1H,m), 5.65 (1H, d, J=8Hz), 6.76-7.72 (13H, m), 7.98 (1H, d, J=16Hz), 8.76(1H, s)

MASS : m/e=441 (M⁺)

[α]_(D) ²⁵ =23.17° (C=0.902 MeOH)

(7)(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-nitrophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 215°-220° C. (dec.)

IR (Nujol) : 3300, 1670, 1650, 1630, 1550, 1520 cm⁻¹

NMR (CDCl₃, δ): 3.15-3.47 (2H, m), 3.96-4.12 (1H, m), 4.61-4.72 (1H, m),5.6 (1H, d J=7.8Hz), 6.56 (1H, d, J=15.5Hz) 6.99-8.17(13H, m)

(8)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-chlorophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 153°-160° C. (dec.)

IR (Nujol) : 3300, 1675, 1650, 1620, 1520 cm⁻¹

NMR (CDCl₃, δ) : 3.09-3.57 (2H, m), 3.97-4.72 (1H, m), 4.60-4.72 (1H,m), 5.59 (1H, d, J=8Hz), 6.61 (1H, d, J=16Hz), 6.99-7.71 (13H, m)

MASS : m/e=459° (M⁺)

(9)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(N-phenylglycyl)amino]-4-oxopyrrolo-[3,2,1-jk][1,4]benzodiazepine

m.p : 135°-137° C. (dec.)

IR (Nujol) : 3450, 3125, 1675, 1650, 1600, 1530 cm⁻¹

NMR (CDCl₃, δ) : 3.06-3.18 (2H, m), 3.89-4.07 (1H, m), 4.57-4.68 (1H,m), 5.48 (1H, d, J=8Hz), 6.7-7.65 (15H, m), 8.21 (1H, d, J=8Hz)

MASS : m/e=4.28 (M⁺)

(10)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-fluorophenyl)propenoylamino]-4oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 186°-193° C.

NMR (CDCl₃, δ) : 3.09-3.47 (2H, m), 3.95-4.11 (1H, m), 4.6-4.73 (1H, m),5.59 (1H, d, J=8Hz), 6.56 (1H, d, J=16Hz), 6.99-7.7 (13H, m)

MASS : m/e=443 (M⁺)

(11)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-nitrophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p. : 267°-269° C.

IR (Nujol) : 3300, 1650, 1630, 1595, 1530, 1510 cm⁻¹

NMR (CDCl₃, δ) : 3.19-3.4 (2H, m), 4.02-4.08 (1H, m), 4.62-4.72 (1H, m),5.58 (1H, d, J=8Hz), 6.72 (1H, d, J=16Hz), 7.0-7.78 (12H, m), 8.26 (1H,d, J=9Hz)

MASS : m/e=470 (M⁺)

(12)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-methylphenyl)propenoylamino]-4oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 224°-225° C.

IR (Nujol) : 3250, 1680, 1650, 1600, 1520 cm⁻¹

NMR (CDCl₃, δ) : 2.37 (3H, s), 3.08-3.46 (2H, m), 3.95-4.11 (1H, m),4.61-4.71 (1H, m), 5.6 (1H, d, J=8Hz), 6.59 (1H, d, J=16Hz), 6.98-7.72(13H, m)

MASS : m/e=439 (M⁺)

(13 (3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(3,4-dichlorophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 250°-252° C.

IR (Nujol) : 3270, 1670, 1650, 1620, 1540 cm⁻¹

NMR (CDCl₃, δ) : 3.10-3.47 (2H, m), 3.96-4.11 (1H, m), 4.61-4.71 (1H,m), 5.57 (1H, d, J=8Hz), 6.62 (1H, d, J=16Hz), 6.99-7.69 (12H, m)

MASS : m/e=493 (M⁺)

(14)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-methoxyphenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 230°-233° C.

IR (Nujol) : 3350, 1655, 1625, 1600, 1510 cm⁻¹

NMR (CDCl₃, δ) : 3.08-3.46 (2H, m), 3.84 (3H, s), 3.95-4.11 (1H, m),4.61-4.71 (1H, m), 5.60 (1H, d, J=8Hz), 6.5 (2H, d, J=16Hz), 6.89-7.71(13H, m)

MASS : m/e=455 (M⁺)

(15)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-chlorophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 137°-140° C. (dec.)

IR (Nujol) : 3250, 1670, 1650, 1635, 1540 cm⁻¹

NMR (CDCl₃, δ) : 3.09-3.47 (2H, m), 3.95-4.11 (1H, m), 4.61-4.73 (1H,m), 5.6 (1H, d, J=8Hz), 6.6-6.67(1H, d, J=16Hz), 6.98-7.71 (12H, m),8.09 (1H, d, J=16Hz)

MASS : m/e=459 (M⁺)

(16)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(3-chlorophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 130°-135° C. (dec.)

IR (Nujol) : 3350-3100, 1690, 1660, 1630 cm⁻¹

NMR (CDCl₃, δ) : 3.09-3.47(2H, m), 3.95-4.11 (1H, m), 4.61-4.77 (1H, m),5.58 (1H, d, J=8Hz), 6.64 (1H, d, J=16Hz), 6.99-7.67 (13H, m)

MASS : m/e=459(M⁺)

(17) (3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-nitrophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

m.p : 170°-185° C. (dec.)

IR (Nujol) : 3260, 1670 cm⁻¹

NMR (CDCl₃, δ) : 3.09-3.47 (2H, m), 3.94-4.11 (1H, m), 4.61-4.72 (1H,m), 5.60 (1H, d, J=8Hz), 6.57 (1H, d, J=15Hz), 6.99-7.72 (11H, m),8.02-8.17 (2H, m)

(18)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(3,4-dihydroxyphenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3550-3000, 1650, 1600, 1510 cm⁻¹

NMR (CDCl₃, δ) : 3.09-3.46(2H,m), 3.90-4.00(1H,m) 4.44-4.54(1H,m),5.41(1H, d, J=8Hz), 5.43-6.50 (1H, b), 6.98-7.61(9H,m), 8.01(1H, s),9.25(1H, s), 9.69(1H, d, J=8Hz)

(19)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-imidazolyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk[1,4]benzodiazepinehydrochloride

IR (Nujol) : 3650-3100, 2750-2200, 1670, 1630, 1600, 1500 cm⁻¹

NMR (DMSO-d₆, δ) : 3.09-3.46(2H, m), 3.90-4.00(1H, m), 4.44-4.54(1H, m),5.41(1H, d, J=8Hz), 5.43-6.50 (1H, b), 6.98-7.61(9H,m), 8.01(1H,s),9.25(1H, s), 9.69 (1H, d, J=8Hz)

(20)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-](E)-3-(2-aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3400, 3350, 3125, 1690, 1640, 1600, 1540 cm⁻¹

(21)(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) 3280, 1670, 1645, 1615, 1545 cm⁻¹

(22)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3250, 1675 1640, 1580, 1530 cm⁻¹

(23) (3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-carboxyindol-3-yl)propenoylamino]-4oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3250 1700 (sh), 1675, 1645, 1610, 1525, 1450, 1370, 1205,985, 835, 745 cm⁻¹

(24)(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[[3-(4-(2-hydroxyethyl)piperazin-1-yl)methyl]indol-2-yl]carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3250, 1690, 1620, 1450, 1372, 1141, 1050, 740 cm⁻¹

(25)(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[[3-(N,N-dimethylaminomethyl)indol-2-yl]carbonylamino]-4oxopyrrolo[3,2,1-jk][1,4]-benzodiazeprnehydrochloride

NMR (DMSO-d₆, δ) : 2.72-2.78 (6H, m), 3.17-3.43 (2H, m), 4.02 (1H, q,J=10.8Hz), 4.52 (1H, t, J™11.4Hz), 4.74 (2H, ABq), 5.59 (1H, d,J=7.7Hz), 7.1-8.0 (11H, m), 9.41 (1H, broad s), 9.83 (1H, d, J=7.7Hz)

(26)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-acetamidophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

NMR (CDCl₃, δ) : 2.21 (3H, s), 3.07-3.36 (2H, m), 3.92-4.08 (1H, m),4.58-4.69 (1H, m), 5.52 (1H, d, J=8Hz), 6.56 (1H, d, J=15Hz), 6.99-7.89(13H, m)

(27)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(3-formylindol-2-yl)carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3200, 1678, 1640, 1580, 1445, 748 cm⁻¹

(28)(3RS)-3,4,6,7-Tetrahyiro-1-(2-fluorophenyl)-3-[(3-hydroxyiminomethylindol-2-yl)carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

NMR (DMSO-d₆, δ) : 3.1-3.5 (2H, m), 4.00 (1H, q, J=10Hz), 4.53 (1H, t,J=10Hz), 5.57 (1H, d, J=7.6Hz), 7.05-8.6 (11H, m), 8.97 (1H, s), 10.07(1H, d, J=7.6Hz), 11.02 (1H, s), 12.16 (1H, s)

(29)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepinehydrochloride

IR (Nujol) : 3600-3100, 2650-2100, 1670, 1610 cm⁻

(30) (3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-4oxopyrrolo[3,2,1-jk][1,4]benzodiazepinehydrochloride

IR (Nujol) : 3600-3100, 2600-2200, 1660, 1610 cm⁻¹

EXAMPLE 15

To a solution of(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-amino-4-oxopyrrolo[3,2,1-jk][1,4benzodiazepine (177.7 mg) in N,N-dimethylformamide (4 ml) were added(E)-3-(2-ethoxycarbonyl-3-indolyl)propenoic acid (156.0 mg),N-ethyl-N'-(3-hydroxybenzotriazole (81.4 mg),N-ethyl-N'-(3-dimethylaainopropyl)carbodiimide hydrochloride (115.4 mg)and triethylamine (60.9 mg) under stirring at ambient temperature. Themixture was stirred for, 4 hours and allowed to stand overnight. Thereaction mixture was poured into a mixture of ethyl acetate and waterunder stirring. The separated organic layer was washed with water twiceand dried. The solvent was removed under reduced preessure to give anamorphous residue, which was subjected to column chromatography onsilica gel with an eluent of a mixture of chloroform and methanol(100:1). The fractions conta,ining the desired product were combined andevaporated to afford a glassy substance, which was pulverized in amixture of diethyl ether and methanol. The powder was collected byfiltration and dried under reduced pressure to give pure(3RS)-3,4,6,7-tetrahydro-1-(,2-fluorophenyl)-3-[(E)-3-(2-ethoxycarbonylindol-3-yl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(148.3 mg).

IR (Nujol) : 3250, 3180, 1710, 1670, 1605, 1530, 1450, 1240, 1212, 740cm⁻¹

NMR (CDCl₃, δ) : 1.42. (3H, t, J=7.1Hz), 3.1-3.4 (2H, m), 4.03 (1H, q,J=10.9Hz), 4.42 (2H, q, J=7.1Hz), 4.66 (1H, t, J=10.9Hz), 5.70 (1H, d,J=8.0Hz), 6.84 (1H, d, J=16.0Hz), 6.8-7.7 (11H, m), 8.00 (1H, d,J=8.0Hz), 8.53 (1H, d, J=16Hz), 9.66 (1H, s).

MASS: m/e=536 (M⁺)

EXAMPLE 16

The following compound was obtained according to a similar manner tothat of Example 15.(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(3-phenyliminomethylindol-2-yl)carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

NMR (CDCl₃, δ) : 3.0-3.5 (2H, m), 3.8-4.2 (1H, broad q), 4.5-4.8 (1H,broad t), 5.74 (1H, d, J=7.5Hz), 6.8-7.8 (16H, m), 8.0 (1H, d, J=7.5Hz),10.4 (1H, s), 10.9 (1H, broad s).

MASS : m/e=541 (M⁺)

EXAMPLE 17

To a solution of coumaric acid (0.68 g) and N-methylmorpholine (0.46 ml)in a mixture of methylene chloride and N,N-dimethylformamide (10:1, 52ml) was added dropwise isobutyl chloroformate (0.54 ml) under stirringat -5° C. The mixture was stirred under the same condition for 15minutes. A solution of(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-amino-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(1.0 g) in a mixture of methylene chloride and N,N-dimethylformamide(10:1, 9 ml) was added to the mixture under stirring at 0° C. Themixture was stirred for 1.5 hours at 0° C. and for 14.5 hours at ambienttemperature. After removal of methylene chloride from the reactionmixture, a saturated aqueous solution of sodium bicarbonate (50 ml) andethyl acetate (50 ml) were added to the residue under stirring. Theseparated organic layer was washed with water and dried over magnesiumsulfate. Removal of the solvent gave an amorphous mass, which wassubjected to column chromatography on silica gel eluting with a mixtureof chloroform and methanol (50:1). The fractions containing the desiredproduct were combined and evaporated. The residue was stirred indiisopropyl ether for several hours, collected by filtration, washedwith diisopropyl ether and dried under reduced pressure to give(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-hydroxyphenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(853 9 mg) as a white powder.

mp: 239°-241° C. (dec.)

IR (Nujol) : 3325, 3200-3000, 1670, 1655, 1610, 1600, 1510 cm⁻¹

NMR (CDCl₃, δ) : 2.8-3.5 (2H, m), 3.8-4.3 (1H, m), 4.43-4.93 (1H, m),5.62 (1H, d, J=8Hz), 6.67-8.1 (14H, m), 8 57 (1H, bs)

MASS: m/e=441 (M⁺)

EXAMPLE 18

To a suspended mixture of iron powder (3.68 g) and ammonium chloride(0.44 g) in a mixture of water (9.2 ml) and ethanol (27.6 ml) was addedportionwise(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-nitrophenyl)propenoylamino]-4-oxopyrrolo3,2,1-jk][1,4]benzodiazepine(3.68 g) under stirring and refluxing. After additional ethanol (10 ml)and water (3.4 ml) were added to the mixture, the resultant mixture wasrefluxed under stirring for 2.5 hours. The reaction mixture was filteredthrough Celite and washed with hot ethanol several times. From thefiltrate and the washings, ethanol was removed under reduced pressure.To the residual mixture was added a saturated aqueous solution of sodiumbicarbonate (100 ml), and the mixture was extracted with chloroform. Theextract was washed with water, dried over magnesium sulfate andevaporated to give a crystalline residue, which was pulvarized withdiisopropyl ether (100 ml) and collected by filtration to afford(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine (1.56 g) as anyellow powder.

mp: 237°-240° C. (dec.)

IR (Nujol) 3400, 3350, 3125, 1690, 1640, 1600, 1540 cm⁻¹

NMR (CDCl₃, δ) : 3.08-3.45 (2H, m), 3.95-4.14 (3H, m), 4.60-4.71 (1H,m), 5.6 (1H, d, J=8Hz), 6.51-7.87 (14H, m)

MASS: m/e=440 (M⁺)

EXAMPLE 19

The following compounds were obtained according to a similar manner tothat of Example 18.

(1)(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-4oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp: 228°-230° C. (dec.)

IR (Nujol) : 3280, 1670, 1645, 1615, 1545 cm⁻¹

NMR (CDCl₃, δ) : 3.08-3.45 (2H, m), 4.00 (2H, s), 3.94-4.10 (1H, m),4.60-4.71 (1H, m), 5.06 (1H, d, J=7.9Hz), 6.55 (1H, d, J=15.4Hz),6.67-7.68 (12H, m), 7.83 (1H, d, J=15.5Hz)

[α]_(D) ²⁵ =13.02° (C=0.86, CHCl₃)

MASS: m/e=440 (M⁺)

(2)(3RS)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(4-aminophenyl)propenoylamino]-4oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

mp: 227°-228° C.

IR (Nujol) : 3250, 1675, 1640, 1580, 1530 cm⁻¹

NMR (CDCl₃, δ) : 3.16-3.33 (4H, m), 4.00-4.10 (1H, m), 4.61-4.67 (1H,m), 5.61 (1H, d, J=7Hz), 6.38-7.72 (14H, m)

MASS: m/e=440 (M⁺)

EXAMPLE 20

To 0.1N aqueous sodium hydroxide (7.5 ml) was dropwise added asuspension of(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-ethoxycarbonylindol-3-yl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(268.3 mg) in 95% ethanol (10 ml) under stirring and refluxing. Theresultant mixture was refluxed for 15 minutes. From the cooled reactionmixture, ethanol was removed under reduced pressure. To the residue wasadded water and the mixture was acidified with diluted hydrochloricacid. The mixture was extracted with ethyl acetate. The extract waswashed with water twice and dried over magnesium sulfate. Removal of thesolvent gave a crystalline powder, which was washed with diethyl etherunder stirring and collected by filtration to give(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-carboxyindol-3-yl)-propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepine(192.0 mg).

mp: 215°-218° C. (dec.)

IR (Nujol) : 3250, 1700 (sh), 1675, 1645, 1610, 1525, 1450, 1370, 1205,985, 835, 745 cm⁻¹

NMR (DMSO-d₆, δ) : 3.1-3.4 (2H, m), 4.00 (1H, q, J=10:8Hz), 4.51 (1H, t,J=10,8Hz), 5.43 (1H, d, J=8Hz), 7.0-7.6 (12H, m), 8.25 (1H, d, J=8Hz),8.47 (1H, d, J=16Hz), 9.39 (1H, d, J=8Hz), 12.14 (1H, s), 13.53 (1H,broad s).

EXAMPLE 21

(1) To a solution of 1-(2-hydroxyethyl)piperazine (156.2 mg) andparaformaldehyde (37.9 mg) in acetic acid (4 ml) was added(3S)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(438.5 mg) under stirring at room temperature. The mixture was heated atabout 85° C. for 3 hours. After removal of acetic acid, to the residuewas added an aqueous solution of sodium bicarbonate and the mixture wasextracted with ethyl acetate. The extract was washed withwater twice anddried over magnesium sulfate. The solvent was removed under reducedpressure to give a viscous oil (0.68 g), which was chromatographed onsilica gel with an eluent of a mixture of chloroform and methanol (50 1)to give colorless oil (494.5 mg). This oil was triturated in ether togive(3S)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[[3-[(4-(2-hydroxyethyl)piperazin-1-yl)methyl]-indol-2-yl]carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine

IR (Nujol) : 3250, 1690, 1620, 1450, 1372, 1141, 1050, 740 cm⁻¹

NMR (CDCl₃, δ) : 2.28 (2H, t, J=5.2Hz), 2.53 (4H, br.s), 2.68 (4H,br.s), 3.07-3.19 (1H, m), 3 44 (2H, t, J=5.2Hz), 3.2-3.5 (1H, m),3.8-4.1 (3H, m), 4.6-4.7 (1H, m), 5.77 (1H, d, J=7.7Hz), 7.0-7.8 (12H,m), 9.79 (1H, s), 12.46 (1H, d, J=7.7Hz)

MASS: m/e=580 (M⁺)

(2) The compound obtained in Example 21(1) was treated with etherealhydrogen chloride in methanol to give(3S)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[[3-[(4-(2-hydroxyethyl)piperazin-1-yl)methyl]indol-2yl]carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepinedihydrochloride (0.25 g).

mp: 225°-232° C.

[α]_(D) ²⁵ : 13.0° (C=0.40, MeOH)

EXAMPLE 22

(1) To a solution of N,N,N',N'-tetramethyldiaminomethane (143.1 mg) indichloromethane (2 ml) was added dropwise acetyl chloride (109 9 mg)under cooling in an ice bath and stirring. The mixture was stirred underthe same condition for one hour. To the resultant mixture was added(3S)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(438.5 mg) under stirring at room temperature. The mixture was stirredfor 4.5 hours at the same temperature. The solvent (dichloromethane) wasremoved by evaporation and to the residue was added water. The aqueousmixture was adjusted to pH 7.5-8 with a saturated aqueous solution ofsodium bicarbonate and extracted with ethyl acetate twice and theextract was washed with water three times. After the extract was driedover magnesium sulfate, the solvent was removed under reduced pressureto afford viscous oil (0.61 g), which was purified by columnchromatography on silica gel with an eluent of a mixture of chloroformand methanol (100:1) to give (3S)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[[3-(N,N-dimethylaminomethyl)indol-2-yl]carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepine(0.6 g).

(2) The compound obtained in Example 22 (1) was treated with etherealhydrogen chloride in methanol to give(3S)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[[3-(N,N-dimethylaminomethyl)indol-2-yl]carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepinehydrochloride (0.52 g) as an yellow powder.

[α]_(D) ²⁵ =83.0° (C=1.0, MeOH)

NMR (DMSO-d₆, δ) : 2.72-2.78 (6H, m), 3.17-3.43(2H, m), 4.02 (1H, q,J=10.8Hz), 4.52 (1H, t, J=11.4Hz), 4.74 (2H, ABq), 5.59 (1H, d,J=7.7Hz), 7.1-8.0 (11H, m), 9.41 (1H, broad s), 9.83 (1H, d, J=7.7Hz).

EXAMPLE 23

To a suspended solution of(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)--3-[(E)-3-(2-aminophenyl)-propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine (0.5 g) anddry pyridine (0.28 ml) in methylene chloride (15 ml) was added dropwiseacetyl chloride (0.12 ml) under stirring and cooling in an ice-bath. Theresultant clear solution was stirred for 0.5 hour under the samecondition and for 2 hours at ambient temperature. The reaction mixturewas washed with water, 1N hydrochloric acid and brine. The organic layerwas dried over magnesium sulfate and evaporated under reduced pressureto give oil, which was chromatographed on silica gel eluting with amixture of chloroform and methanol (50:1). The fractions containing thedesired product were combined and evaporated. The residue was pulverizedin diisopropyl ether, collected by filtration, washed with diisopropylether and dried under reduced pressure at 50° C. for 6 hours to give(3RS)-3,4,.6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-acetamidophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine (372 mg) as a white powder.

mp: 180°-189° C.

NMR (CDCl₃, δ) : 2.21 (3H, s), 3.07-3.36 (2H, m), 3.92-4.08 (1H, m),4.58-4.69 (1H, m), 5.52 (1H, d, J=8Hz), 6.56 (1H, d, J=15Hz), 6.99-7.89(13H, m)

MASS: m/e=482 (M⁺)

EXAMPLE 24

To a suspension of(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(3-phenyliminomethylindol-2-yl)carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(1.73 g) in ethanol (30 ml) was added 2N hydrochloric acid (20 ml). Themixture was stirred under at 55° C. for 2 hours. The reaction mixturewas cooled in an ice bath for 0.5 hour, and yellow precipitates werecollected by filtration, washed with water and dried to give(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(3-formylindol-2-yl)carbonylamino]-4-oxopyrrolo[3,2,1-jk]-[1,4]benzodiazepine(1.44 g).

IR (Nujol) : 3200, 1678, 1640, 1580, 1445, 748 cm⁻¹

NMR (DMSO-d₆, δ): 3.1-3.5 (2H, m), 4.02 (1H, q, J=10Hz), 4;53 (1H, t,J=10Hz), 5.58 (1H, d, J=7.5Hz), 7.05-8.3 (11H, m), 10.54 (1H, s), 11.30(1H, d, J=7.5Hz), 12.95 (1H, s)

MASS: m/e=466 (M⁺)

EXAMPLE 25

To a suspension of(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(3-formylindol-2-yl)carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(466 mg) in glacial acetic acid (35 ml) were added successivelyhydroxylamine hydrochloride (208 5 mg) and sodium acetate (246 1 mg)under stirring at room temperature. The mixture was warmed understirring at 70° C. for 8.5 hours and evaporated under reduced pressure.To the residue was added water and the resultant precipitates werecollected by filtration and washed with water twice and cold methanol togive(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl-3-[(3-hydroxyiminomethylindol-2-yl)carbonylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(379.1 mg).

mp: >250° C.

NMR (DMSO-d₆, δ) : 3.1-3.5 (2H, m), 4.00 (1H, q, J=10Hz), 4.53 (1H, t,J=10Hz), 5.57 (1H, d, J=7.6Hz), 7.05-8.6 (11H, m), 8.97 (1H, s), 10.07(1H, d, J=7.6Hz), 11.02 (1H, s), 12.16 (1H, s).

MASS: m/e=481 (M⁺)

EXAMPLE 26

To a solution of(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepine(0.5 g) in chloroform (30 ml) was added a mixture of 6N hydrochloricacid and ether (30 ml). The mixture was evaporated under reducedpressure. The residue was washed with ethanol three times and withdiisopropylether once. The residue was pulverized in diisopropyl etherand the mixture was stirred for one hour. The resultant powder wascollected by filtration, washed with diisopropyl ether and dried underreduced pressure to give(3RS)-3,4,6,7-tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]-benzodiazepinehydrochloride

mp: 199°-203° C. (dec.) IR (Nujol): 3600-3100, 2650-2100, 1670, 1610cm⁻¹

NMR (DMSO-d₆, δ) : 3.1-3.63 (2H, m), 3.9-4.0 (1H, m), 4.45-4.55 (1H, m),5.41 (1H, d, J=8Hz), 7.04-7.78 (15H, m), 9.46 (1H, d, J=8Hz)

MASS : m/e=440 (M⁺ -36)

EXAMPLE 27

The following compound was obtained according to a similar manner tothat of Example 26.(3S)-3,4,6,7-Tetrahydro-1-(2-fluorophenyl)-3-[(E)-3-(2aminophenyl)propenoylamino]-4-oxopyrrolo[3,2,1-jk][1,4]benzodiazepinehydrochloride.

mp: 190°-195° C. (dec.)

IR (Nujol) : 3600-3100, 2600-2200, 1660, 1610 cm⁻¹

NMR (CDCl₃, δ) : 3.18-3.46 (2H, m), 3.96-4.01 (1H, m), 4.44-4.54 (1H,m), 5.41 (1H, d, J=8Hz), 7.04-7.78 (15H, m), 9.45 (1H, d, J=8Hz),

[α]_(D) ²⁵ : 46.81° (C=0.848, MeOH)

MASS : m/e=440 (M⁺ -36)

What we claim is:
 1. A compound of the formula: ##STR18## wherein R¹ isaryl which may have suitable substituent(s), X is --O-- or ##STR19## inwhich R³ is hydrogen or lower alkyl, A is bond; or methylene, ethylene,trimethylene, tetramethylene, pentamethylene or hexamethylene, each ofwhich may have lower alkyl group(s), andR² is heterocyclic(C₃-C₆)alkenoyl in which the heterocyclic group is selected from the groupconsisting of pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl,tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl,isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, oxazolyl, isoxazolyl,oxadiazolyl, morpholinyl, sydnonyl, benzoxazolyl, benzoxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl,thienyl, dihydrodithiinyl, benzothiazolyl, benzothiadiazolyl, furyl,dihydrooxanthiinyl, benzothienyl, benzodithiinyl and benzoxathiinyl,each of which may have carboxy or protected carboxy as a substituent; orheterocycliccarbonyl in which the heterocyclic group is selected fromthe group consisting of pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl,pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl,tetrazolyl, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl,isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, oxazolyl, isoxazolyl,oxadiazolyl, morpholinyl, sydnonyl, benzoxazolyl, benzoxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolidinyl,thienyl, dihydrodithiinyl, benzothiazolyl, benzothiadiazolyl, furyl,dihydrooxathiinyl, benzothienyl, benzodithiinyl and benzoxathiinyl, eachof which may have N,N-di(lower)alkylamino(lower)alkyl,hydroxyimino(lower) alkyl, arylimino(lower)alkyl, acyl or hydroxy(lower)alkylheterocyclic(lower alkyl as a substituent, or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1,wherein R² isimidazolyl (C₃ -C₆)alkenoyl; quinolyl (C₃ -C₆)alkenoyl;quinolylcarbonyl; or indolinylcarbonyl.
 3. A cholecystokinin antagonistpharmaceutical composition which comprises, as an active ingredient, aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof in admixture with a pharmaceutically acceptablecarrier.
 4. A method for treating or preventing emesis or pancreatitiswhich comprises administering an effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof to a human or animal.